The most common inherited human disorder causing blindness is retinitis piqmentosa, and the most common cause of blindness in persons over the age of 60 is age-related macular degeneration. Blindness in both families of diseases is caused by photoreceptor cell death. At present, no widely accepted form of therapy exists for these diseases. Two experimental therapeutic approaches are proposed to prevent photoreceptor cell death in animal models, the delivery of neurotrophic factors to the photoreceptors by gene transfer using recombinant adeno-associated viral (AAV) vectors, and the delivery by gene transfer to photoreceptors of ribozymes, small catalytic RNA molecules that can reduce the production of harmful mutant proteins produced by dominant gene mutations. Each of these approaches has been effective in initial studies to reduce the degree of photoreceptor cell loss in animal models of retinal degeneration. This proposal aims at clarifying many key questions that relate to the new experimental therapeutic approaches, including: are protective agents efficacious in multiple animal models; are combinations of neurotrophic factors more effective than single agents; at which stage(s) of the disease are the approaches effective; are retinal degenerations with slower rates of cell loss more responsive to therapy than those with faster rates; are combinations of therapeutic approaches more effective than single approaches? These questions will be explored using intraocular injections of AAV vectors followed by functional (electroretinography and multifocal electroretinography) and structural (quantitative histology) analysis of the retina. The additional question of whether the rescue of photoreceptors and photoreceptor function with the therapeutic approaches results in preservation of vision will be addressed by the analysis of retinal sensitivity (assessed by central visual physiology) and visual acuity (using physiological and behavioral methods). Similarly, the visual consequences of negative structural and functional retinal changes caused by the neurotrophic factor, CNTF, will be assessed by physiological and behavioral methods. The molecular mechanisms of photoreceptor rescue by neurotrophic factors will also be explored by determining the role of retinal Muller cells in promoting photoreceptor survival by knocking down expression of specific qenes in Muller cells using RNA interference.